Cue-induced craving is currently not well understood in nicotine dependence, and is a poor predictor of use. However, as with other drugs of abuse, studies suggest that craving measures become more relevant to drug use when the opportunity to use more closely follows the measurement. Furthermore, previous studies of cue-induced craving have used visual, auditory, and some tactile cues, which may lose salience. The fact that the first cranial (olfactory) nerve has a direct connection to the limbic region of the central nervous system suggests that odors may play a significant role in cue-induced craving and so olfactory cues may evoke a more potent response than other modalities. This R21 proposal focuses on the effects of visual and olfactory cues on medium cigarette smokers. Using functional magnetic resonance imaging (fMRI), we will examine the brain circuitry and activity patterns involved in the responses to these cues during satiety and short-term abstinence. Generalized linear models (GLM) are the standard analysis method for functional scans. However, GLM methods by design ignore fluctuations about the modeled brain response, and this variability is itself of interest. Independent component analysis (ICA) offers a new method to analyze these data sets, particularly suitable for capturing these complex fluctuations in neural activity. Therefore, employing ICA to analyze the resulting data will reveal spatiotemporal brain patterns of craving and related states that are not visible using conventional analyses. We will conduct a prospective cue-induced craving fMRI experiment in which moderate smokers (15-25 cigarettes/day) will experience both visual and olfactory smoking-related cues (contrasted with similar stimuli without smoking valence), during both satiety and short-term abstinence. ICA and GLM methods will be compared in an effort to provide a better understanding of the role that olfactory cues play in relapse in general and to tobacco smoking in particular. We anticipate that olfactory cues will yield a larger effect that visual ones, particularly in regions previously associated with craving, and that ICA analysis methods will be more sensitive to these cue- induced changes than will GLM techniques. The most effective cues and analysis methods found with the present exploratory study will be used in a future R01 grant application examining cue-related brain activation of smokers during the first month after quitting. Follow-up studies will examine the role of quit aids, duration and intensity of smoking, comorbid disorders, and sex-related differences on the predictive value of activation patterns for long-term quit rates. PUBLIC HEALTH RELEVANCE: Millions of American cigarette smokers want to quit, but have not achieved long-term abstinence because they relapse to use. A better understanding of the process of how tobacco-related cues, especially odors, result in relapse to smoking would permit the development of more effective treatment strategies that can be individually tailored. The use of new brain mapping tools will allow such relationships to be identified.